Standard therapy for a variety of immune and inflammatory disorders includes administration of corticosteroids, which have the ability to suppress immunologic and inflammatory responses. Corticosteroids are used in the treatment of disorders such as asthma, autoimmune diseases (e.g., rheumatoid arthritis, systemic lupus erythematosus) and transplant rejection (for reviews on corticosteroids, see e.g., Truhan, A. P. et al. (1989) Annals of Allergy 62:375-391; Baxter, J. D. (1992) Hospital Practice 27:111-134; Kimberly, R. P. (1992) Curr. Opin. Rheumatol. 4:325-331; Weisman, M. H. (1995) Curr. Opin. Rheumatol. 7:183-190). Corticosteroids are also used topically in the treatment of various dermatological disorders, such as contact dermatitis, psoriasis vulgaris, lichen planus, keloids and urticaria pigmentosa (for a review, see Sterry, W. (1992) Arch. Dermatol. Res. 284 (Suppl.):S27-S29).
While therapeutically beneficial, the use of corticosteroids is associated with a number of side effects, ranging from mild to possibly life threatening. Complications associated with prolonged and/or high dose steroid usage include musculoskeletal effects (e.g., osteoporosis, myopathy, aseptic necrosis of bone), ophthalmic effects (e.g., posterior subcapsular cataracts), gastrointestinal effects (e.g., ulcers, pancreatitis, nausea, vomiting), cardiovascular effects (e.g., hypertension, atherosclerosis), central nervous system effects (e.g., pseudotumor cerebri, psychiatric reactions), dermatological effects (e.g., hirsutism, redistribution of subcutaneous fat, impaired wound healing, thinning of the skin) and suppression of the hypothalamus-pituitary-adrenal axis (see e.g., Truhan, A. P. et al. (1989) Annals of Allergy 62:375-391). Many of the side effects of corticosteroid usage appear to be dose-dependent (Kimberly, R. P. (1992) Curr. Opin. Rheumatol. 4:325-331). Accordingly, methods and compositions that enable the use of a lower effective dosage of corticosteroids (referred to as the "steroid sparing effect") would be highly desirable to avoid unwanted side effects.
Another problem that limits the usefulness of corticosteroids is the phenomenon of steroid resistance. Certain inflammatory or immunological diseases exhibit refractoriness to steroid treatment. For example, attempts to use corticosteroid therapy to treat septic shock in humans have met with disappointing results and thus corticosteroids are not generally recommended as adjunctive therapy in severe sepsis or septic shock (see e.g., Putterman, C. (1989) Israel J. Med. Sci. 25:332-338; Bone, R. C. and Brown, R. C. (1990) in Vincent, J. L. (ed.) "Update in Intensive Care and Emergency Medicine 10", Heidelberg:Springer Verlag, p. 121). Other disorders that often exhibit resistance to corticosteroid treatment include inflammatory bowel disease (see e.g., Hibi, T. et al. (1995) J. Gastroenterol. 30:121-123) and graft-versus-host disease (Antin, J. H. et al. (1994) Blood 84:1342-1348; Racadot, E. et al. (1995) Bone Marrow Transplantation 15:669-677). Thus, methods and compositions that can be used to overcome or reverse corticosteroid resistance in inflammatory and immunological disorders are still needed.
Yet another disadvantage of corticosteroid therapy is the occurrence of a "steroid rebound effect" when corticosteroid administration is discontinued. A steroid rebound effect is characterized by the worsening of the inflammatory condition(s) being treated upon cessation of steroid therapy. Methods and compositions that can be used to ameliorate the steroid rebound effect are still needed.